Electrophilic amination with iminomalonate

Article abstract of DOI:10.1016/S0040-4039(01)01022-X

Diethyl N-anisyliminomalonate has been found to be an excellent electrophilic amination reagent for Grignard reagents to give N-alkylated products in good yields, and subsequent air oxidation affords N-alkylanisidines.

Full text of DOI:10.1016/S0040-4039(01)01022-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 5473–5476
Electrophilic amination with iminomalonate
Yasuki Niwa, Kazuki Takayama and Makoto Shimizu*
Department of Chemistry for Materials, Mie University, Tsu, Mie 514-8507, Japan
Received 11 May 2001; revised 4 June 2001; accepted 8 June 2001
Abstract—Diethyl N-anisyliminomalonate has been found to be an excellent electrophilic amination reagent for Grignard reagents
to give N-alkylated products in good yields, and subsequent air oxidation affords N-alkylanisidines. © 2001 Elsevier Science Ltd.
All rights reserved.
Although one of the most important reactions for the
preparation of amines involves electrophilic amination
of anions, such reactions have not been readily carried
out due to the tedious preparation and instability of
reagents, lack of the generality, and so on.1 Recent
studies in this field have found several efficient elec-
trophilic aminations with imine derivatives such as
oxaziridines,2 oximes,3 and oxime O-sulfonates.4 How-
ever, there still remains important problems of accessi-
bility of the reagent as well as of the reaction
procedure. Hitherto, several reagents have been devel-
oped for N-alkylation reactions of a-imino esters.5 In
particular, Grignard reagents were proved to be the
reagents of choice for this type of N-alkylation reaction
of a-imino esters.5a In our laboratory, we recently
described the coupling reaction of a-iminoacetates with
dialkylaluminum chloride to give N-monoalkylated 1,2-
diamines, where efficient N-alkylation with alkylalu-
minum reagents was highly responsible for the success
of the new coupling reaction.6 During these studies we
found that imines with two electron-withdrawing sub-
stituents possessed good abilities to react with nucleo-
philes on the nitrogen atoms in a regioselective manner.
We wish to report that N-anisyliminomalonate 1 is
a new efficient electrophilic amination reagent for
Grignard reagents to give, after subsequent oxidation
with air, N-alkylanisidines 5 in good to excellent yields
(Fig. 1).
First, addition of several ethylation reagents is exam-
ined and the results are summarized in Table 1. Ethyl-
aluminum dichloride and diethylaluminum chloride
gave the desired N-ethylation product 3a in 32 and 66%
yield, respectively with good regioselectivity, whereas
diethylzinc in toluene solution afforded 3a in 80% yield
along with the C-ethylation product 4a (entries 1, 2 and
5). The use of ethylmagnesium bromide recorded the
formation of the N-ethylation product 3a in 84% yield
(entry 6). From the standpoint of accessibility of the
alkylation reagents, Grignard reagents were chosen as
nucleophiles in the present study. After screening of the
solvent and the amount of Grignard reagent, the use of
1.5 equiv. of ethylmagnesium bromide in THF was
found to be the most effective to give the N-ethylation
product 3a in 91% yield (entry 9).
We next examined oxidative removal of the malonate
moiety to obtain N-ethylanisidine 5a, and results are
summarized in Table 2.
pAn
R
CO2Et
CO2Et
pAn
R
N
H
CO2Et
CO2Et
N
pAnN
1
5
3
Figure 1.
The amination reagent, diethyl N-anisyliminomalonate
1 was prepared by condensation of commercially avail-
able diethyl ketomalonate 27 with p-anisidine in 85%
yield (Scheme 1).
CO2Et
CO2Et
CO2Et
CO2Et
pAnNH2 (1.1 eq), TsOH (5 mol%)
O
pAnN
MS4A, Benzene, reflux
Y. 85%
1
2
* Corresponding author. Tel.: +81-59-231-9413; fax: +81-59-231-9413;
e-mail: mshimizu@chem.mie-u.ac.jp
Scheme 1.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01022-X

5474
Y. Niwa et al. / Tetrahedron Letters 42 (2001) 5473–5476
Table 1. Ethylation of iminomalonate 1 using several organometals
CO2Et
Et-Met
pAn
Et
CO2Et pAnNH CO2Et
pAnN
N
-78 oC
CO2Et
CO2Et
Et CO2Et
4a
3a
1
Entry
Et-Met (equiv.)
Solvent
Time (min)
Yield of 3a (%)a
Yield of 4a (%)a
1
2
3
4
5
6
7
8
9
EtAlCl2 (3)
Et2AlCl (3)
Et3Al (3)
Et2Zn (3)
Et2Zn (3)
EtMgBr (1.2)
EtMgBr (1.2)
EtMgBr (1.2)
EtMgBr (1.5)
CH2Cl2
CH2Cl2
CH2Cl2
THF
Toluene
THF
Et2O
Toluene
THF
65
18
42
56
17
60
10
17
48
32
66
25
40
80
84
59
50
91
–
–
24
23
15
–
–
–
–
a Yields were determined by 1H NMR using pyrazine as internal standard.
Table 2. Oxidative cleavage of N-ethylation product 3a
pAn
CO2Et
CO2Et
pAn
Et
Oxidant
Base - EtOH
N
N
H
Et
3a
Base
5a
Entry
Oxidant (equiv.)
Temp. (°C)
Time (h)
Yield (%)a
1
2
3
4
5
6
PhI(OAc)2 (1.5)
PhI(OTfa)2 (1.5)
KOH (2 M)
KOH (2 M)
KOH (2 M)
1 M KOH aq (0.44 equiv.)
1 M KOH aq (0.44 equiv.)
1 M KOH aq (0.44 equiv.)
0ꢀrt
0ꢀrt
0ꢀrt
rt
rt
rt
17
26
22
48
47
22.5
22
54
82
57
84
45
PhIO (1.5)
Air
Airb
O2
a Isolated yields.
b Worked up with 10% aqueous Na2SO3.
Although iodosobenzene diacetate, known as a mild
oxidation reagent for a-hydroxylation of carbonyl com-
pounds, was firstly examined,8 N-ethylanisidine 5a was
obtained in only 22% yield (entry 1). Iodosobenzene
was found to be an effective oxidation reagent for this
reaction to give the desired product 5a in 82% yield
(entry 3).9 Since oxidation with air is more inexpensive
and convenient,10 air oxidation was next used for the
present transformation to give N-ethylanisidine 5a in
57% yield (entry 4). The yield was improved up to 84%
by working up the crude reaction mixture with 10%
aqueous Na2SO3 (entry 5). In contrast, the use of
oxygen itself was not effective to this oxidative cleavage
(entry 6).
desired product (entry 8). When isopropylation reaction
was carried out at −95°C, the yield was improved up to
46%. However, the use of tertiary alkylmagnesium bro-
mide did not give the N-alkylation product in satisfac-
tory yield, and the oxidative cleavage did not proceed
at all (entry 10). The use of phenylmagnesium bromide
met with a moderate success (entry 13).
In conclusion, diethyl N-anisyliminomalonate was
found to be a good electrophilic amination reagent for
alkylmagnesium halides. In particular, this reagent was
effective for the amination of primary alkyl Grignard
reagents, whereas those of secondary, tertiary alkyl,
and aryl Grignard reagents gave the desired products in
slightly lower yields. The subsequent oxidative removal
of malonate moiety was readily carried out with air,
giving N-alkylanisidines and oxomalonate which might
be used repeatedly. From the standpoint of electrophilic
amination, this is the first example where a-imino ester
is used as the practical amination reagent possessing a
removable N-p-anisyl group. Furthermore, this regent
enables the ready separation of the products, anisidine
derivatives, from the reaction mixture due to the
lipophilic anisyl moiety.
The use of a variety of Grignard reagents followed by
oxidative cleavages was examined, and the results are
summarized in Table 3. Alkylation with primary alkyl
Grignard reagents proceeded to give N-alkylation prod-
ucts, and the subsequent oxidative cleavage also pro-
ceeded smoothly to give N-alkylanisidines in good to
excellent yields (entries 1–7), whereas the use of iso-
propylmagnesium bromide gave the N-alkylation
product in 34% yield along with the C-alkylated by-
product, resulting in the decrease in the yield of the

Y. Niwa et al. / Tetrahedron Letters 42 (2001) 5473–5476
Table 3. Synthesis of N-alkylanisidine with electrophilic aminationa
5475
CO2Et
CO2Et
pAn
R
CO2Et
CO2Et
pAn
R
R-MgBr
THF, -78 oC
Air
pAnN
N
N
H
KOHaq - EtOH
1
3
5
Entry
R
Products
Yield of 3 (%)b,c
Yield of 5 (%)d
1
2
3
4
5
6
7
8
Methyl
Ethyl
n-Propyl
n-Butyl
n-Decyl
n-Dodecyl
n-Tetradecyl
Isopropyl
Cyclohexyl
tert-Butyl
Phenethyl
Benzyl
3b, 5b
3a, 5a
3c, 5c
3d, 5d
3e, 5e
3f, 5f
3g, 5g
3h, 5h
3i, 5i
81
91
81
87
78
94
79
34 (46)
36 (38)
25
86
57 (63)
44
50
84
79
60
79
84
71
68
78
9
e
10
11
12
13
3j, 5j
3k, 5k
3l, 5l
–
89
80
99
Phenyl
3m, 5m
a The reaction was carried out according to the typical procedure (Ref. 11).
b Yields were determined by 1H NMR using pyrazine as internal standard.
c Yields in the parentheses were obtained from the runs carried out at −95°C.
d Isolated yields.
e Oxidative cleavage did not proceed.
Acknowledgements
rien, M. J.; Murdoch, J. R. J. Am. Chem. Soc. 1984,
106, 5753.
.
5. (a) Fiaud, J.-C.; Kagan, H. B. Tetrahedron Lett. 1971,
1019; (b) Yamamoto, Y.; Ito, W. Tetrahedron 1988, 44,
5415; (c) Uneyama, K.; Yan, F.; Hirama, S.; Katagiri,
T. Tetrahedron Lett. 1996, 37, 2045; (d) Bertrand, M.
P.; Feray, L.; Nouguier, R.; Perfetti, P. Synlett 1999,
1148.
This work was supported by a Grant-in-Aid for Scien-
tific Research from the Ministry of Education, Science,
Sports, and Culture, of the Japanese Government and a
grant from Nagase Science and Technology
Foundation.
6. Shimizu, M.; Niwa, Y. Tetrahedron Lett. 2001, 42,
2829.
References
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11. <Ethylation reaction>Under an argon atmosphere, to a
solution of diethyl N-anisyliminomalonate (83.8 mg,
0.300 mmol) in THF (3.75 mL), EtMgBr (0.450 mmol,
0.971 M in THF) was slowly added at −78°C. After 48
min, saturated aqueous NaHCO3 was added, and the
whole mixture was then extracted with ethyl acetate (10
mL×3). The combined organic extracts were washed
with brine, dried over anhydrous Na2SO4, and concen-
trated in vacuo. Yield was determined by 1H NMR
using pyrazine as an internal standard to indicate the

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Y. Niwa et al. / Tetrahedron Letters 42 (2001) 5473–5476
formation of diethyl 2-(N-ethyl-N-anisylamino)malonate
mixture. EtOH was then evaporated, and the residue
was extracted with ethyl acetate (10 mL×3). The com-
bined organic extracts were washed with brine, dried
over anhydrous Na2SO4, and concentrated in vacuo.
The crude product was purified on preparative silica gel
TLC (AcOEt/hexane=1:10) to give N-ethylanisidine
(30.3 mg, 84%).
in 91%.
<Oxidative cleavage>The crude diethyl 2-(N-ethyl-N-
anisylamino)malonate (0.240 mmol) was dissolved in a
mixture of 1.0 M KOH (0.106 mL) and EtOH (3.06
mL), and the whole solution was vigorously stirred.
After 47 h, 10% aqueous Na2SO3 was added to this
.